Traumatic brain injury (TBI) is a complex, life-threatening condition that causes mortality and disability worldwide. No effective treatment has been clinically verified to date. Achieving effective drug delivery across the blood-brain barrier (BBB) presents a major challenge to therapeutic drug development for TBI. Furthermore, the field of TBI biomarkers is rapidly developing to cope with the many aspects of TBI pathology and enhance clinical management of TBI. Exosomes (Exos) are endogenous extracellular vesicles (EVs) containing various biological materials, including lipids, proteins, microRNAs, and other nucleic acids. Compelling evidence exists that Exos, such as stem cell-derived Exos and even neuron or glial cell-derived Exos, are promising TBI treatment strategies because they pass through the BBB and have the potential to deliver molecules to target lesions. Meanwhile, Exos have decreased safety risks from intravenous injection or orthotopic transplantation of viable cells, such as microvascular occlusion or imbalanced growth of transplanted cells. These unique characteristics also create Exos contents, especially Exos-derived microRNAs, as appealing biomarkers in TBI. In this review, we explore the potential impact of cell-derived Exos and exosome-derived microRNAs on the diagnosis, therapy, and prognosis prediction of TBI. The associated challenges and opportunities are also discussed.